ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.376T>A (p.Tyr126Asn) (rs200076893)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524295 SCV000254369 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 126 of the MLH1 protein (p.Tyr126Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is present in population databases (rs200076893, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in the literature in individuals affected with Lynch syndrome (PMID: 18561205, 24383517). ClinVar contains an entry for this variant (Variation ID: 90184). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 22290698). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000217922 SCV000279071 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.376T>A at the cDNA level, p.Tyr126Asn (Y126N) at the protein level, and results in the change of a Tyrosine to an Asparagine (TAC>AAC). This variant was observed in at least one individual with early-onset, microsatellite instable colorectal cancer (Stigliano 2014). MLH1 Tyr126Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MLH1 Tyr126Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000410157 SCV000489372 uncertain significance Lynch syndrome II 2016-09-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571582 SCV000662020 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000571582 SCV000684824 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing

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